A TOLERANCE APPROACH TO XENOTRANSPLANTATION

描述（由申请人提供）：异种器官移植提供了最好的近期希望，以满足目前由于尸体同种异体器官严重短缺而对移植领域施加的关键限制。我们在本项目资助的前一个项目期间的研究取得了相当大的进展，从猪到狒狒的心脏和肾脏异种移植的器官存活现在以月为单位，而不是以天为单位。这种存活率提高的一个主要因素是一种新型的微型猪敲除菌株（GalT-KO）的发展，这种菌株在细胞上不表达Gal表位，从而避免了以前由天然抗Gal抗体引起的严重排斥。我们还表明，使用这些新供体的器官存活率的最大改善是使用旨在诱导耐受性的方案。然而，在这项技术准备好用于临床应用之前，还需要进一步的改进。这项更新申请汇集了五个项目，致力于该领域研究中最有前途的方法和最紧迫的问题：1)通过血管化胸腺移植诱导耐受性；2)混合嵌合诱导耐受性；3)建立具有人类免疫系统的小鼠耐受性模型；病毒在异种移植中的发病机制；5)异种移植的血栓调节障碍。所有这些项目都是高度互动的，并利用许多共享资源，其中许多将通过大型动物核心提供。这项工作将在一个独特的环境中进行，它提供了与在同一研究中心从事基础和细胞免疫学工作的科学家以及从事相关小型和大型动物模型研究的科学家以及致力于将新疗法用于临床应用的临床医生的互动。

DESCRIPTION (provided by applicant): Xenotransplantation offers the best near-term hope for satisfying the critical limitation imposed on the field of transplantation today by the severe shortage of cadaveric allogeneic organs. Our studies in the previous Project period of this Program Project grant have made considerable progress, and organ survivals of both heart and kidney xenotransplants from pigs to baboons are now measured in months rather than days. A major factor in this improved survival has been the development of a new, knock-out strain of miniature swine (GalT-KO), which do not express the Gal epitope on their cells, thus avoiding the severe rejection previously caused by natural anti-Gal antibodies. We have also shown that the greatest improvement in organ survivals using these new donors is observed using protocols designed to induce tolerance. Nevertheless, additional improvements will be required before this technology is ready for clinical application. This renewal application brings together five Projects devoted to the most promising approaches and the most pressing problems in this field of research: 1) tolerance induction through vascularized thymic transplantation; 2) tolerance induction through mixed chimerism; 3) modeling of tolerance in mice with human immune systems; 4) Viral pathogenesis in Xenotransplantation; and 5) thromboregulatory barriers to Xenotransplantation. All of these Projects-are highly interactive, and utilize numerous shared resources, many of which will be made available through the large animal core. The work will be carried out in a unique environment, which provides interactions with scientists working in basic and cellular immunology and working on relevant small and large animal models in the same research center, as well as with clinicians committed to taking new therapies to clinical applications. PROJECT 1: Use of GalT-KO Vascularized Thymic Transplantation for the Induction of Xenogeneic Tolerance in Baboons (Yamada, K.) PROJECT 1 DESCRIPTION (provided by applicant): The overall objective of Project 1 is to induce durable tolerance across a pig-to-baboon xenogeneic barrier through transplantation of vascularized thymic grafts. For this purpose, we will: 1) optimize our immunosuppressive drug regimen: We have demonstrated previously that vascularized thymic grafts support thymopoiesis and induce transplant tolerance across fully mismatched allogeneic barriers. In this xenogeneic model, we will attempt to optimize the immunomodulatory treatment regimen required to achieve durable thymus engraftment; 2) determine whether the engrafted thymus can induce tolerance to a kidney xenograft from an inbred donor animal genetically identical to the thymus donor. If successful, the strategy will be extended to simultaneous thymus plus kidney xenotransplantation; and 3) elucidate the mechanism of donor thymus-induced tolerance, using in vitro assays and focusing on the specificity of tolerance across this species barrier. These studies will be highly interactive with other Projects in this PPG. Thus, the optimal treatment regimen will be modified, if necessary, on the basis of results from a mouse model of pig-to-primate tolerance through thymus transplantation being investigated by Sykes and colleagues in Project 3. If eventual antibody-mediated rejection cannot be effectively prevented through thymic transplantation, we will attempt to induce B-cell tolerance by combining thymic transplantation with hematopoietic transplantation, being studied in Project 2. We will also collaborate with Project 5 on the mechanism of any post-transplant coagulation disorders observed. Together, we hope these studies will provide new insights into the potential role of thymic transplantation in the induction of transplantation tolerance.